CN104250255A - Flexible lactam macrocycle molecule and preparation method thereof - Google Patents

Flexible lactam macrocycle molecule and preparation method thereof Download PDF

Info

Publication number
CN104250255A
CN104250255A CN201310267695.5A CN201310267695A CN104250255A CN 104250255 A CN104250255 A CN 104250255A CN 201310267695 A CN201310267695 A CN 201310267695A CN 104250255 A CN104250255 A CN 104250255A
Authority
CN
China
Prior art keywords
formula
flexible
lactams
aryl
macrocycle molecule
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201310267695.5A
Other languages
Chinese (zh)
Other versions
CN104250255B (en
Inventor
张强
崔晓杰
谭伟
陈瀚
袁谷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peking University
Original Assignee
Peking University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peking University filed Critical Peking University
Priority to CN201310267695.5A priority Critical patent/CN104250255B/en
Publication of CN104250255A publication Critical patent/CN104250255A/en
Application granted granted Critical
Publication of CN104250255B publication Critical patent/CN104250255B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Abstract

The present invention discloses a flexible lactam macrocycle molecule and a preparation method thereof, wherein the structure general formula is represented by a formula I, A is one selected from pyrrolyl, 1,4-dimethylene-1,2,3-triazolyl, phenyl, pyridyl, imidazolyl and N-methyl imidazolyl, R is H or -(CH2)nR', R' is one selected from amino, C1-C6 alkyl amino, C5-C7 aryl, C5-C10 heterocyclic aryl and C6-C10 arylamino, and n is an integer of 1-3. The flexible lactam macrocycle molecule preparation method adopts the half long-chain substrate containing the alkyne-azide bifunctional group to carry out intermolecular cyclization through the clicking reaction, is different from the traditional preparation method adopting the full long-chain precursor to carry out intramolecular ring closing, and has advantages of simple synthesis method, green, high efficiency and the like. The formula I is defined in the instruction.

Description

A kind of flexible lactams macrocycle molecule and preparation method thereof
Technical field
The present invention relates to lactams macrocycle molecule, particularly by the flexible lactams macrocycle molecule of a class that click-reaction efficiently synthesizes.
Background technology
In chemistry, biology and field of medicaments, lactams macrocycle molecule is very popular research focus, comprises as (Nicolaou, K.C. such as antibiotic vancomycins; Vourloumis, D.; Winssinger, N.; Baran, P.S., The art and science of total synthesis at the dawn of the twenty-first century.Angew Chem Int Edit2000,39, (1), 44-122; Service, R.F., Race for molecular summits.Science1999,285, (5425), 184-187.), cyclic peptide and derivative thereof are also large class lactams molecules in addition.Research finds that lactams macrocycle molecule has the unusual drug effect such as anticancer, antibacterial, antiviral, has medicinal application prospect more widely (Sarabia, F.; Chammaa, S.; Ruiz, A.S.; Ortiz, L.M.; Herrera, F.J.L., Chemistry and biology of cyclic depsipeptides of medicinal and biological interest.CurrMed Chem2004,11, (10), 1309-1332; Zhu, J.P., Recent developments in reversing glycopeptide-resistant pathogens.Expert Opin Ther Pat1999,9, (8), 1005-1019; He, H.T.; Xu, C.R.; Song, X.; Siahaan, T.J., Syntheses of cyclic prodrugs ofRGD peptidomimetics with various macrocyclic ring sizes:evaluation of physicochemical, transport and antithrombic properties.J Pept Res2003,61, (6), 331-342.).In addition, lactams macrocycle molecule is also important fundamental construction molecule (Alfonso, I. in the research of supramolecule device; Bolte, M.; Bru, M.; Burguete, M.I.; Luis, S.V.; Rubio, J., Supramolecular control for the modular synthesis of pseudopeptidic macrocycles through an anion-templated reaction.Journal of the American Chemical Society2008,130, (19), 6137-6144.).The source of lactams macrocycle molecule except extracting from natural product, engineer, synthesis are also important acquisition methods, in view of the important function of lactams macrocycle molecule, beta-lactams synthesis macrocycle molecule is a very popular research field in organic chemistry.Traditional large ring synthesis step is complicated, need to carry out ring closure reaction under extremely low concentration of substrate, long reaction time and side reaction is many, reaction yield is lower, and cyclization is comparatively large by the impact of intermediate composition composition, linear substrate length and three-dimensional arrangement, therefore still has very large research space on synthetic methodology.
The expression of c-myb gene in the malignant tumours such as leukemia will far away higher than normal cell (Oh, 1.H.; Reddy, E.P. The myb gene family in cell growth, differentiation and apoptosis.Oncogene, 1999,18, (19), 3017-3033.), carry out suppressing effectively to control the proliferation and spreading of cancer cells to the expression of c-myb gene, and form G-tetra-serobila by the rich guanine sequence of this gene promoter area of induction and stablize expression (Palumbo, the S.L. that this structure can suppress this gene significantly; Memmott, R.M.; Uribe, D.J.; Krotova-Khan, Y.; Hurley, L.H.; Ebbinghaus, S.W.A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity.Nucleic Acids Res., 2008,36, (6), 1755-1769.).Lactams macrocycle molecule has selective binding and stabilization (Zhang Q. to G-tetra-serobila being positioned at the rich guanine sequence formation in c-myb gene promoter area to have bibliographical information to show; Cui X.; Lin S.; Zhou J.; Yuan G.Convenient method for the synthesis of a flexible cyclic polyamide for selective targeting of c-myb G-quadruplex DNA.2012,14, (24), 6126-6129.), therefore this quasi-molecule is the potential drug lead compound of the malignant tumours such as treatment leukemia.
Summary of the invention
The object of this invention is to provide a kind of starting raw material simple, the synthetic method of the efficient flexible lactams macrocycle molecule fast of building-up process, and this kind of macrocycle molecule can Selective recognition c-myb gene promoter area G-tetra-stranded structure.
The flexible lactams macrocycle molecule general structure of the present invention's synthesis is as shown in the formula I:
In formula I, A is selected from the one in pyrryl, Isosorbide-5-Nitrae-dimethylene 1,2,3-triazoles base, phenyl, pyridyl, imidazolyl and N-methylimidazolyl; R is H or-(CH 2) nr ', wherein R ' is selected from the one in the aryl amine of amino, the alkylamino of C1 ~ C6, the aryl of C5 ~ C7, the heterocyclic aryl of C5 ~ C10 and C6 ~ C10; N is the integer of 1-3.
Alkylamino such as methylamino, dimethylamino, Pyrrolidine base, piperidyl, morpholinyl, piperazinyl, the N methyl piperazine base etc. of above-mentioned C1 ~ C6.
Aryl such as phenyl, chloro-phenyl-, bromophenyl, the nitrophenyl etc. of above-mentioned C5 ~ C7.
Above-mentioned C5 ~ C10 heterocyclic aryl such as pyrryl, imidazolyl, furyl, thienyl, pyridyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-and benzothiazolyl etc.
Aryl amine such as aminophenyl, methylamino phenyl, the dimethylaminophenyl etc. of above-mentioned C6 ~ C10.
When the A in formula I is pyrryl, its general structure is as shown in the formula shown in IA:
In formula IA, when R is hydrogen, its structure as shown in Equation 1, called after cPT; When R is-CH 2nH 2time, its structure as shown in Equation 2, called after cPTN.
When the A in formula I is Isosorbide-5-Nitrae-dimethylene 1,2,3-triazoles base, its general structure is as shown in the formula shown in IB:
In formula IB, when R is hydrogen, its structure as shown in Equation 3, called after cTz; When R is-CH 2nH 2time, its structure as shown in Equation 2, called after cTN.
Shown in formula I of the present invention, compound is prepared by following method: (the formula II), by the interconnective mode of amido linkage alkynyl group and azido group on its carbon, nitrogen two ends respectively coupling to protect N-terminal fundamental construction molecule from shown tertbutyloxycarbonyl (Boc) below; Then the short chain precursor (formula IV) of the carbon teminal alkynyl group obtained and nitrogen endlap nitrogen groups is carried out intermolecular reaction cyclisation by the click-reaction (Huisgen cycloaddition reaction) of monovalence copper catalysis, and through certain aftertreatment as deprotection base etc. obtains compound shown in shown formula I.
In above-mentioned reaction formula, R " is H or the aforementioned R group with protecting group.
Above-mentioned preparation method uses and carries out intermolecular cyclization containing alkynes-nitrine bifunctional group half long-chain substrate by click-reaction, is different from the large lopps molecule of tradition and first synthesizes the preparation method that then full long chain precursors carries out intramolecular cyclization.The reaction type that the inventive method is brought into use from initiator is less, also more fast easy in synthetic method, has the advantages such as synthetic method is simple, green high-efficient.
Formula I of the present invention is potential cancer therapy drug lead compound, can be used for the medicine preparing the malignant tumours such as treatment leukemia.Found by electrospray ionization mass spectrum (ESI-MS) experiment, the compound cPT (compound 1) of the present invention's synthesis and cTN (compound 4) is to c-myb gene promoter area rich guanine sequence 5 '-(GGA) 8-3 ' G-tetra-serobila formed has keying action.Illustrate that the flexible macrocycle molecule of lactams that the present invention is obtained by simple high efficiency method has the possibility becoming the treating malignant tumor lead compound such as leukemia.
Accompanying drawing explanation
Fig. 1 is cPT (compound 1) and c-myb promoter region G-tetra-serobila (Q1,5 '-(GGA) 8-3 ' the electrospray ionization mass spectrum spectrogram combined) is identified;
Fig. 2 is cTN (compound 4) and c-myb promoter region G-tetra-serobila (Q1,5 '-(GGA) 8-3 ' the electrospray ionization mass spectrum spectrogram combined) is identified.
Embodiment
Below by specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is ordinary method if no special instructions.Described starting material all can obtain from open commercial sources if no special instructions.
Pyrroles used in the present invention is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.Boc acid anhydrides, HOBt (I-hydroxybenzotriazole), HBTU (2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester), BOP (benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate), DIEA (DIPEA) are purchased from Shanghai covalency company limited.Palladium carbon is purchased from Alfa Aesar.Trifluoroacetic acid, cuprous chloride are purchased from lark prestige company.S-isoserine is purchased from Beijing Chemical Co., Ltd. of Hua Weirui section.Propargylamine, N, N '-dimethyl quadrol (DIMED) is purchased from Shanghai Sa En-An Naiji chemical reagent company limited.The common solvent such as other medicines such as anhydrous sodium sulphate, sodium hydride, sodium hydroxide, trichoroacetic acid(TCA), diacetyl oxide, ethyl bromoacetate, sodium azide and chloroform, methyl alcohol, ethyl acetate, sherwood oil, methylene dichloride, acetone, DMF (dimethyl formamide), tetrahydrofuran (THF) are purchased from Beijing chemical reagents corporation.Column chromatography silica gel (200-300 order), thin layer silica gel column chromatography plate are purchased from Haiyang Chemical Plant, Qingdao.
One, the preparation of fundamental construction molecule pyrrole derivative (compound 9):
Reaction formula:
Be that initiator successively carries out tribromo-acetyl and nitrated introducing carbon teminal group and nitrogen end group group respectively with pyrroles, then protect through over-churning, catalytic hydrogenation and amido Boc, last saponification acidifying obtains fundamental construction molecular compound 9.
1. the synthesis of intermediate 5:
Get 30mL pyrroles (29.1g, 433mmol) and be placed in constant pressure funnel, add 90mL ether, mixing.Get 45mL trichoroacetic chloride (73.2g, 431mmol) and be placed in there-necked flask, add 120mL ether, mixing.There-necked flask is placed in ice-water bath cool, slowly instill the diethyl ether solution stirring reaction of pyrroles when passing into nitrogen, within about 2.5 hours, dropwise, reaction system slowly rises to room temperature and continues reaction 3.5 hours.Unsaturated carbonate potassium solution cancellation reaction is added in reaction system.With extracted with diethyl ether aqueous phase twice, merge organic phase, by water and saturated common salt water washing organic phase, be spin-dried for after anhydrous sodium sulfate drying.The thick product n-hexane obtained and suction filtration obtains white solid product 5 (66.3g, 313mmol, 72%). 1hNMR (300MHz, DMSO-d 6): δ 12.46 (s, 1H), 7.36 (m, 1H), 7.32 (m, 1H), 6.37 (m, 1H). 13cNMR (100MHz, DMSO-d 6): δ 172.0,129.2,121.8,121.3,111.3,95.4.LRMS (ESI-Ion Trap): m/z210.0 ([M-H] -, C 6h 3cl 3nO calculated value is 209.9).
2. the synthesis of intermediate 6:
Intermediate 5 (44.5g, 210mmol) is dissolved in 250mL diacetyl oxide, reaction flask is placed in dry ice-ethanol bath and is cooled to-40 DEG C.Slowly drip 18.5mL70% concentrated nitric acid stirring reaction with constant pressure funnel, within about 2.5 hours, dropwise, after dropwising, reaction system is cooled to-40 DEG C after approximately spending within 2.5 hours, slowly rise to room temperature again.Add frozen water rapidly and filter to obtain light brown deposit crude product.With sherwood oil: ethyl acetate=5: 2 (v/v) for eluent by crude product quickly through the dry post of silica gel (flash column chromatography) Chromatographic purification, ethyl acetate and sherwood oil recrystallization is used after being spin-dried for organic solvent, filtration obtains white solid product 6 (28.6g, 111mmol, 53%). 1h NMR (300MHz, DMSO-d 6): δ 13.67 (s, 1H; Pyrrole NH), 8.40 (d, 3j (H, H)=1.5Hz, 1H), 7.72 (d, 3j (H, H)=1.5Hz, 1H). 13cNMR (100MHz, DMSO-d 6): δ 172.9,137.1,127.7,121.4,114.3,93.8.LRMS (ESI-Ion Trap): m/z255.0 ([M-H] -, C 6h 2cl 3n 2o 3calculated value is 254.9).
3. the synthesis of intermediate 7:
Be dissolved in by intermediate 6 (21g, 82mmol) in 100mL ethanol and be cooled to 0 DEG C with ice-water bath, add sodium hydride (2.0g, 83mmol), temperature of reaction rises to room temperature naturally in batches, continues stirring reaction 3 hours.Add 3mL vitriol oil cancellation reaction, add rapidly 1.5L frozen water, separate out a large amount of white precipitate, filter and obtain white solid product 7 (15g, 81mmol, 99%). 1h NMR (300MHz, DMSO-d 6): δ 13.16 (s, 1H), 8.09 (d, 3j (H, H)=1.8Hz, 1H), 7.26 (d, 3j (H, H)=1.8Hz, 1H), 4.29 (q, 3j (H, H)=7.2Hz, 2H), 1.31 (t, 3j (H, H)=7.2Hz, 3H). 13c NMR (100MHz, DMSO-d 6): δ 159.4,136.6,124.2,122.9,109.3,60.7,14.1.LRMS (ESI-Ion Trap): m/z183.1 ([M-H] -, C 7h 7n 2o 4calculated value be 183.0).
4. the synthesis of intermediate 8:
By compound 7 (14.5g, 78.8mmol) be dissolved in 200mL ethyl acetate, add 2.5g10% palladium-carbon catalyst, add 25mL methyl alcohol deactivated catalyst, be full of hydrogen after charge and discharge hydrogen three times in reaction system, at 40 DEG C, vigorous stirring reacts 8 hours, after TLC monitoring reaction completes, reaction system is cooled to room temperature, uses rapidly diatomite filtration removing palladium carbon, revolve except a part of solvent concentration system is to 100mL.Add Boc acid anhydrides (35g, 161mmol) and DIEA (10g, 78.7mmol), the reaction of nitrogen protection stirred at ambient temperature is spent the night.Reaction system is used anhydrous sodium sulfate drying with after saturated common salt water washing, is spin-dried for, the thick product ethyl acetate obtained and sherwood oil recrystallization, filter and obtain white solid product 8 (18.4g, 72.4mmol, 92%). 1h NMR (300MHz, DMSO-d 6): δ 11.52 (s, 1H), 9.10 (s, 1H), 6.95 (s, 1H), 6.60 (s, 1H), 4.20 (q, 3j (H, H)=7.2Hz, 2H), 1.44 (s, 9H), 1.26 (t, 3j (H, H)=7.2Hz, 3H). 13c NMR (100MHz, DMSO-d 6): δ 160.4,152.8,125.0,119.3,112.5,105.4,78.4,59.4,28.1,14.3.LRMS (ESI-Ion Trap): m/z253.2 ([M-H] -, C 12h 17n 2o 4calculated value be 253.1).
5. the synthesis of fundamental construction molecular compound 9:
By compound 8 (8.6g, 34mmol) be dissolved in 100mL methyl alcohol, add 100mL1M sodium hydroxide solution, stirring reaction 5 hours at 40 DEG C, vacuum is revolved except methyl alcohol, drips 2M hydrochloric acid soln and regulates about pH to 2, filtering-depositing, appropriate washed with diethylether is used to obtain white solid product 9 (7.0g, 31mmol, 91%). 1h NMR (300MHz, DMSO-d 6): δ 12.17 (s, 1H), 11.35 (s, 1H), 9.04 (s, 1H), 6.92 (s, 1H), 6.55 (s, 1H), 1.44 (s, 9H). 13c NMR (100MHz, DMSO-d 6): δ 161.9,152.8,124.9,120.2,112.2,105.5,78.4,28.2.LRMS (ESI-Ion Trap): m/z225.1 ([M-H] -, C 10h 13n 2o 4calculated value be 225.1).
Two, the preparation of raw material nitrine acetic acid:
Reaction formula:
The synthesis of compound 10:
Under ice-water bath, 20.0g ethyl bromoacetate (120mmol) is dissolved in 20mL DMF, add sodium azide (12.5g in batches, 192mmol), naturally rise to room temperature reaction and add saturated sodium carbonate solution after 24 hours, extracted with diethyl ether three times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, colourless transparent liquid is obtained after being spin-dried for, be dissolved in 60mL methyl alcohol, add 60mL1M sodium hydroxide solution, reacting at 40 DEG C revolved except methyl alcohol after 5 hours, with washed with diethylether aqueous phase twice, by aqueous phase with in 2M hydrochloric acid soln and about pH to 2, extracted with diethyl ether three times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, light yellow transparent liquid product 10 (4.9g is obtained after being spin-dried for, 48.5mmol, 81%). 1h NMR (400MHz, CDCl 3): δ 6.97 (s, 1H), 3.95 (s, 2H). 13c NMR (100MHz, CDCl 3): δ 172.3,50.1.LRMS (ESI-Ion Trap): m/z100.0 ([M-H] -, C 2h 2n 3o 2calculated value be 100.0).
Three, the preparation of raw material nitrine acetogenin:
Reaction formula:
1. the synthesis of intermediate 11:
50.0g S-isoserine (476mmol) is dissolved in 200mL ethanol, continue to pass into HCl gas 5 hours under ice-water bath cooling, naturally rise to stirring at room temperature reaction to spend the night, revolve and filter except adding ether after ethanol, obtained white solid is scattered in 250mL ethyl acetate, triethylamine (130mL is added under ice-water bath, 94.4g, 935mmol) with Boc acid anhydrides (150g, 688mmol), naturally rise to stirring at room temperature reaction to spend the night, revolve after desolventizing and add sherwood oil filtration, obtain the S-t 11 (108g of white solid product Boc protection, 463mmol, 97%).
2. the synthesis of compound 12:
10.0g intermediate 11 (42.9mmol) is dissolved in 100mL methylene dichloride, add triethylamine (12mL, 8.7g, 86.3mmol), Tosyl chloride (9.8g is instilled under ice-water bath, 80mL dichloromethane solution 51.3mmol), naturally rise to stirring at room temperature reaction to spend the night, organic phase uses 1% hydrochloric acid soln successively, saturated sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for, the yellow oil obtained is dissolved in 75mL DMF, add sodium azide (7.0g under room temperature in batches, 108mmol), rise to 60 DEG C of reactions and be cooled to room temperature after 12 hours, add saturated sodium carbonate solution, extraction into ethyl acetate three times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, colourless transparent liquid is obtained after being spin-dried for, be dissolved in 60mL methyl alcohol, add 60mL1M sodium hydroxide solution, reacting at 40 DEG C revolved except methyl alcohol after 5 hours, with washed with diethylether aqueous phase twice, by aqueous phase with in 2M hydrochloric acid soln and about pH to 2, extracted with diethyl ether three times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for freezing after obtain faint yellow solid product 12 (7.1g, 30.9mmol, 72%). 1hNMR (400MHz, CDCl 3): δ 7.80 (d, 3j (H, H)=7.8Hz, 1H), 7.18 (s, 1H), 4.17 (m, 1H), 3.60 (m, 1H), 3.42 (m, 1H), 1.44 (s, 9H). 13c NMR (100MHz, CDCl 3): δ 176.5,171.9,80.7,61.5,41.7,28.3.LRMS (ESI-Ion Trap): m/z229.0 ([M-H] -, C 8h 13n 4o 4calculated value be 229.1).
Four, the preparation of the propargylamine of raw material Boc protection:
Reaction formula:
The synthesis of compound 13
5.5g propargylamine (100mmol) is dissolved in 50mL ethyl acetate, Boc acid anhydrides (32g is added under ice-water bath, 147mmol), naturally rise to stirring at room temperature reaction to spend the night, organic phase uses 1% hydrochloric acid soln, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, be spin-dried for, obtain yellow solid product 13 (15.3g, 99mmol, 99%). 1h NMR (400MHz, CDCl 3): δ 4.75 (s, 1H), 3.90 (d, 3j (H, H)=3.0Hz, 2H), 2.21 (t, 3j (H, H)=3.0Hz, 1H), 1.44 (s, 9H). 13c NMR (100MHz, CDCl 3): δ 155.2,80.2,71.4,30.2,28.2,27.3.LRMS (ESI-Ion Trap): m/z154.0 ([M-H] -, C 8h 12nO 2calculated value be 154.1).
Here is the synthetic example of part of compounds of the present invention:
The synthesis of embodiment one compound 1 and 2
Reaction formula:
1. the synthesis of intermediate 14:
By fundamental construction molecular raw material 9 (1.00g; 4.42mmol), HOBt (0.600g; 4.44mmol) with HBTU (2.50g; 6.60mmol) be dissolved in DMF (7mL); add DIEA (0.7mL; propargylamine (0.42mL is added after 4mmol) reacting 15min; 0.361g; under 6.63mmol) nitrogen protection room temperature, reaction is spent the night; ethyl acetate is added in reaction system; use 1% hydrochloric acid soln, saturated sodium bicarbonate solution and saturated common salt water washing successively, be spin-dried for after anhydrous sodium sulfate drying, through column chromatography (CH 2cl 2: CH 3oH=15: 1-10: 1) purification obtains faint yellow solid product 14 (1.12g, 4.26mmol, 96%). 1hNMR (400MHz, DMSO-d 6): δ 11.10 (s, 1H), 9.01 (s, 1H), 8.42 (t, 3j (H, H)=8.0Hz, 1H), 6.81 (s, 1H), 6.70 (s, 1H), 3.96 (s, 2H), 3.09 (s, 1H), 1.44 (s, 9H). 13c NMR (100MHz, DMSO-d 6): δ 171.6,163.7,155.7,125.7,124.1,113.2,104.0,80.4,30.2,28.2,27.3.LRMS (ESI-Ion Trap): m/z261.9 ([M-H] -, C 13h 16n 3o 3calculated value be 262.1).
2. the synthesis of intermediate 15:
By compound 14 (0.500g, 1.90mmol) join methylene dichloride: trifluoroacetic acid=1: remove in 1 solution (8mL) after Boc protects 1 hour and be spin-dried for, join by nitrine acetic acid 10 (0.290g, 2.87mmol) with BOP (1.90g, 4.29mmol) at DIEA (0.5mL, in DMF (5mL) solution of 3mmol) catalyzed reaction 15min, under nitrogen protection, room temperature reaction spends the night, ethyl acetate is added in reaction system, use 1% hydrochloric acid soln successively, saturated sodium bicarbonate solution and saturated common salt water washing, be spin-dried for after anhydrous sodium sulfate drying, through column chromatography (CH 2cl 2: CH 3oH=15: 1-10: 1) purification obtains faint yellow solid product 15 (0.337g, 1.37mmol, 72%). 1h NMR (400MHz, MeOD-d 4): δ 7.26 (d, 3j (H, H)=7.2,1H), 6.83 (d, 3j (H, H)=7.2,1H), 4.09 (d, 3j (H, H)=4.1,2H), 3.99 (s, 2H), 2.58 (t, 3j (H, H)=4.1,1H). 13c NMR (100MHz, MeOD-d 4): δ 167.2,162.9,124.4,114.6,104.3,81.1,72.0,53.1,29.4,24.3.LRMS (ESI-Ion Trap): m/z245.0 ([M-H] -, C 10h 9n 6o 2calculated value be 245.1).
3. the synthesis of intermediate 16:
Synthetic method with compound 15 is identical, obtains faint yellow solid product 16 (0.390g, 1.04mmol, 55%) by compound 14 (0.500g, 1.90mmol) and nitrine acetogenin 12 (0.660g, 2.87mmol). 1hNMR (400MHz, acetone-d 6): δ 10.62 (s, 1H), 9.45 (s, 1H), 7.75 (s, 1H), 7.38 (s, 1H), 6.92 (s, 1H), 6.38 (s, 1H), 4.14 (s, 2H), 4.13 (s, 1H), 3.64 (m, 1H), 3.44 (m, 1H), 2.64 (s1H), 1.41 (s, 9H). 13c NMR (100MHz, acetone-d 6): δ 165.8,161.2,156.8,124.6,124.5,113.4,102.7,81.7,79.3,71.8,63.3,43.2,28.8,28.6.LRMS (ESI-Ion Trap): m/z374.0 ([M-H] -, C 16h 20n 7o 4calculated value be 374.2).
4. the synthesis of compound 1:
Compound 15 (0.100g, 0.407mmol) is dissolved in 166mL tetrahydrofuran (THF), adds 33mL water, CuCl (20mg successively, 0.202mmol), N, N '-dimethyl quadrol (43 μ L, 35mg, 0.400mmol), now reaction substrate concentration is 2mM.This solution under nitrogen protection stirring at room temperature reacts 1 day, revolves and obtains yellow-brown solid product 1 (0.090g, 0.183mmol, 90%) except filtering the solid obtained after THF through methanol wash. 1hNMR (400MHz, DMSO-d 6): δ 11.44 (s, 2H), 9.98 (s, 2H), 8.28 (s, 2H), 7.92 (s, 2H), 7.01 (s, 2H), 6.91 (s, 2H), 5.13 (s, 4H), 4.49 (s, 4H). 13c NMR (100MHz, DMSO-d 6): δ 162.3,159.9,156.5,123.6,123.4,122.9,111.6,103.0,53.1,34.2.HRMS (ESI-FTICR): m/z493.1791 ([M+H] +, C 20h 21n 12o 4calculated value be 493.1809).
5. the synthesis of compound 2:
Compound 16 (0.150g, 0.400mmol) is dissolved in 166mL tetrahydrofuran (THF), adds 33mL water, CuCl (20mg successively, 0.202mmol), N, N '-dimethyl quadrol (43 μ L, 35mg, 0.400mmol), now reaction substrate concentration is 2mM.This solution under nitrogen protection stirring at room temperature reacts 1 day, revolves and is not removed product before the yellow-brown solid of Boc protecting group except filtering the solid obtained after THF through a small amount of methanol wash.Methylene dichloride will be joined by product before this: trifluoroacetic acid=1: remove in 1 solution (4mL) after Boc protects 1 hour and be spin-dried for; add the saturated ethyl acetate solution of hydrogenchloride; be spin-dried for after ultrasonic 2 minutes; dihydrochloride (the 0.100g obtaining yellow solid product 2 is filtered after adding ether; 0.161mmol, 81%). 1h NMR (400MHz, DMSO-d 6): δ 11.37 (s, 2H), 10.95 (s, 2H), 8.74 (s, 2H), 8.34 (s, 4H), 8.18 (s, 2H), 7.13 (s, 2H), 6.81 (s, 2H), 5.78 (s, 4H), 4.47 (s, 4H), 3.66 (m, 2H), 3.39 (m, 2H). 13c NMR (100MHz, DMSO-d 6): δ 161.5,160.2,123.5,122.8,122.6,112.1,102.5,65.0,60.0,56.0,34.1.HRMS (ESI-FTICR): m/z551.2342 ([M+H] +, C 22h 27n 14o 4calculated value be 551.2340).
The synthesis of embodiment two compound 3 and 4
Reaction formula:
1. the synthesis of intermediate 17:
The propargylamine 13 (12.9mmol) protect 2.0g starting compound Boc and 1.3g nitrine acetic acid 10 (12.9mmol) are dissolved in 10mL THF; add 2mL water, CuCl (0.64g successively; 6.5mmol), N; N '-dimethyl quadrol (1.4mL; 114g; 12.9mmol); react under room temperature after 1 hour and add 2mL2M hydrochloric acid soln; add ethyl acetate; use 1% hydrochloric acid and saturated common salt water washing successively, be spin-dried for after anhydrous sodium sulfate drying, after freezing, obtain white solid product 17 (3.0g; 11.7mmol, 91%). 1h NMR (400MHz, acetone-d 6): δ 11.91 (br, 1H), 7.96 (s, 1H), 6.50 (s, 1H), 5.33 (s, 2H), 4.36 (s, 2H), 1.44 (s, 9H). 13c NMR (100MHz, acetone-d 6): δ 168.8,156.8,124.9,82.0,79.1,51.2,36.7,28.2.LRMS (ESI-Ion Trap): m/z255.0 ([M-H] -, C 10h 15n 4o 4calculated value be 255.1).
2. the synthesis of intermediate 18:
Synthetic method with compound 14 is identical, obtains faint yellow solid product 18 (1.07g, 3.65mmol, 93%) by compound 17 (1.00g, 3.91mmol). 1h NMR (400MHz, MeOD-d 4): δ 7.88 (s, 1H), 5.41 (s, 2H), 4.32 (s, 2H), 3.66 (d, 3j (H, H)=3.0,2H), 2.63 (t, 3j (H, H)=3.0,2H), 1.43 (s, 9H). 13c NMR (100MHz, MeOD-d 4): δ 166.8,147.5,125.9,82.8,82.2,72.3,63.8,42.9,42.2,31.3,28.9.LRMS (ESI-Ion Trap): m/z292.1 ([M-H] -, C 13h 18n 5o 3calculated value be 292.2).
3. the synthesis of intermediate 19:
Synthetic method with compound 15 is identical, obtains faint yellow solid product 19 (0.188g, 0.681mmol, 80%) by compound 18 (0.250g, 0.853mmol). 1hNMR (400MHz, acetone-d 6): δ 7.91 (s, 1H), 5.32 (s, 2H), 4.01 (s, 2H), 3.94 (s, 2H), 3.75 (s, 2H), 2.62 (s, 1H). 13c NMR (100MHz, acetone-d 6): δ 166.8,148.0,126.1,82.8,82.2,63.8,51.2,42.9,42.2,31.3.LRMS (ESI-Ion Trap): m/z275.0 ([M-H] -, C 10h 11n 8o 2calculated value be 275.1).
4. the synthesis of intermediate 20:
Synthetic method with compound 16 is identical, obtains faint yellow solid product 20 (0.245g, 0.605mmol, 71%) by compound 18 (0.250g, 0.853mmol). 1h NMR (400MHz, acetone-d 6: δ 7.90 (s, 1H), 5.33 (s, 2H), 4.16 (s, 2H), 4.14 (s, 1H), 4.36 (s, 2H), 3.64 (m, 1H), 3.44 (m, 1H), 2.64 (s1H), 1.41 (s, 9H). 13cNMR (100MHz, acetone-d 6): δ 165.8,161.2,148.2,126.2,156.1,81.7,79.3,71.8,63.3,51.2,43.2,31.3,28.8,28.6.LRMS (ESI-Ion Trap): m/z404.1 ([M-H] -, C 16h 22n 9o 4calculated value be 404.2).
5. the synthesis of compound 3:
Synthetic method with compound 1 is identical, obtains faint yellow solid product 3 (0.083g, 0.150mmol, 83%) by compound 19 (0.100g, 0.362mmol). 1hNMR (400MHz, DMSO-d 6): δ 8.87 (s, 4H), 7.95 (s, 4H), 5.12 (s, 8H), 4.37 (s, 8H) .LRMS (ESI-FTICR): m/z5511 ([M-H] -, C 20h 23n 16o 4calculated value be 551.2).
6. the synthesis of compound 4:
Synthetic method with compound 2 is identical, is obtained the dihydrochloride (0.097g, 0.142mmol, 77%) of faint yellow solid product 4 by compound 20 (0.150g, 0.370mmol). 1hNMR (400MHz, DMSO-d 6): δ 9.47 (s, 2H), 9.32 (s, 2H), 8.37 (s, 4H), 7.62 (s, 2H), 7.48 (s, 2H), 5.53 (s, 3j (H, H)=5.5,2H), 4.87 (s, 4H), 4.61 (m, 2H), 4.32 (s, 4H), 3.96 (m, 2H). 13c NMR (100MHz, DMSO-d 6): δ 165.4,164.9,145.9,121.7,121.5,60.0,54.1,38.0,34.7,34.4.HRMS (ESI-FTICR): m/z611.2782 ([M+H] +, C 22h 31n 18o 4calculated value be 611.2776).
Here is the Application Example of compound shown in segment bounds I provided by the invention:
Test DNA sequence dna 5 '-(GGA) used 8-3 ' (SEQ ID No:1) is purchased from Sangon Biotech (Shanghai) Co., Ltd..Ammonium acetate is purchased from Beijing chemical reagents corporation.Chromatographic Pure Methanol is purchased from Fisher.Deionized water uses Mill Q Pure water preparation instrument to obtain.
Embodiment three electrospray ionization mass spectrum (ESI-MS) experiment exam compound is to the keying action of c-myb gene promoter area G-tetra-serobila
First DNA sample annealed: be dissolved in by DNA in Spirit of Mindererus, be warming up to 90 DEG C of heating 10 minutes, be then slowly down to room temperature, temperature fall time is greater than 12 hours, G-tetra-serobila conformation (Q1) that this process makes DNA conformation transition become stable.ESI-MS data are measured by Finnigan LCQ DECA XP plus mass spectrograph (Thermo Finnigan, San Jose, CA).DNA sample be evenly diluted in 100mM ammonium acetate, 25% methyl alcohol (v/v) solution, concentration is 10 μMs.CPT (compound 1) is dissolved in the methanol solution containing 10%DMSO (v/v), and cTN (compound 4) is dissolved in deionized water.Negative ion mode is used to detect.Sample introduction speed: 2 μ L/min, spray voltage: 2.7kV, ion transfer tube temperature: 120 DEG C, nitrogen flow rate: 25arb.The acquisition and processing of data uses Xcalibur software and Origin software, often opens spectrogram by the average gained of scanning of 5 minutes.
ESI-MS identifies that experiment finds, cPT (compound 1) and cTN (compound 4) has associativity to c-myb promoter region G-tetra-serobila (Q1), as depicted in figs. 1 and 2, when the molecule mol ratio of G-tetra-serobila (Q1) and macrocycle molecule reaches 1: 4, G-tetra-serobila (Q1) with a cPT (compound 1) molecule in conjunction with peak (m/z, 1649.5) relative intensity can reach about 50%, G-tetra-serobila (Q1) with two cPT (compound 1) molecule in conjunction with peak (m/z, 1747.9) relative intensity can reach about 10% (Fig. 1) respectively, G-tetra-serobila (Q1) can reach about 20% (Fig. 2) with a cTN (compound 4) molecule in conjunction with peak (m/z, 1672.3) relative intensity.This shows that cPT (compound 1) and cTN (compound 4) has the ability becoming c-myb gene promoter area G-tetra-serobila selective binding molecule, and pass through macrocyclic structure, especially the optimization of side-chain structure, these macrocycle molecules likely become the lead compound for the treatment of c-myb gene-associated diseases especially malignant tumour.

Claims (6)

1. the flexible lactams macrocycle molecule shown in formula I:
In formula I, A is selected from the one in pyrryl, Isosorbide-5-Nitrae-dimethylene 1,2,3-triazoles base, phenyl, pyridyl, imidazolyl and N-methylimidazolyl; R is H or-(CH 2) nr ', wherein R ' is selected from the alkylamino of amino, C1 ~ C6, the aryl of C5 ~ C7, the one in the heterocyclic aryl of C5 ~ C10 and the aryl amine of C6 ~ C10; N is the integer of 1-3.
2. flexible lactams macrocycle molecule as claimed in claim 1, is characterized in that, the alkylamino of described C1 ~ C6 is selected from the one in methylamino, dimethylamino, Pyrrolidine base, piperidyl, morpholinyl, piperazinyl and N methyl piperazine base; The aryl of described C5 ~ C7 is selected from the one in phenyl, chloro-phenyl-, bromophenyl and nitrophenyl; Described C5 ~ C10 heterocyclic aryl is selected from the one in pyrryl, imidazolyl, furyl, thienyl, pyridyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-and benzothiazolyl; The aryl amine of described C6 ~ C10 is selected from the one in aminophenyl, methylamino phenyl and dimethylaminophenyl.
3. flexible lactams macrocycle molecule as claimed in claim 1, is characterized in that, this flexible lactams macrocycle molecule is compound shown in formula IA or formula IB:
Wherein R is H or-(CH 2) nr ', wherein R ' is selected from the one in the aryl amine of amino, the alkylamino of C1 ~ C6, the aryl of C5 ~ C7, the heterocyclic aryl of C5 ~ C10 and C6 ~ C10; N is the integer of 1-3.
4. flexible lactams macrocycle molecule as claimed in claim 3, is characterized in that, this flexible lactams macrocycle molecule is one of following formula 1 to formula 4 compound:
5. the preparation method of flexible lactams macrocycle molecule described in claim 1, its reaction formula is as follows:
N-terminal fundamental construction molecule is protected, by the interconnective mode of amido linkage alkynyl group and azido group on its carbon, nitrogen two ends respectively coupling from the tertbutyloxycarbonyl shown in formula II; Then the short chain precursor shown in the formula IV of acquisition is carried out intermolecular reaction cyclisation by the click-reaction of monovalence copper catalysis, and deprotection obtains compound shown in shown formula I; Wherein A and R as claim 1 define; R " is H or the R group with protecting group.
6. the arbitrary described flexible lactams macrocycle molecule of Claims 1 to 4 is preparing the application in cancer therapy drug.
CN201310267695.5A 2013-06-28 2013-06-28 A kind of flexible lactams macrocycle molecule and preparation method thereof Expired - Fee Related CN104250255B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310267695.5A CN104250255B (en) 2013-06-28 2013-06-28 A kind of flexible lactams macrocycle molecule and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310267695.5A CN104250255B (en) 2013-06-28 2013-06-28 A kind of flexible lactams macrocycle molecule and preparation method thereof

Publications (2)

Publication Number Publication Date
CN104250255A true CN104250255A (en) 2014-12-31
CN104250255B CN104250255B (en) 2016-05-25

Family

ID=52185534

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310267695.5A Expired - Fee Related CN104250255B (en) 2013-06-28 2013-06-28 A kind of flexible lactams macrocycle molecule and preparation method thereof

Country Status (1)

Country Link
CN (1) CN104250255B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1430620A (en) * 2000-05-22 2003-07-16 诺瓦提斯公司 Macrolides compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1430620A (en) * 2000-05-22 2003-07-16 诺瓦提斯公司 Macrolides compound

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
QIANG ZHANG等: "Convenient Method for the Synthesis of a Flexible Cyclic Polyamide for Selective Targeting of c‑myb G‑quadruplex DNA", 《ORGANIC LETTERS》 *
QIANG ZHANG等: "Convenient Method for the Synthesis of a Flexible Cyclic Polyamide for Selective Targeting of c‑myb G‑quadruplex DNA", 《ORGANIC LETTERS》, vol. 14, no. 24, 4 December 2012 (2012-12-04), pages 6126 - 6129 *
TUSHAR KANTI CHAKRABORTY等: "Furan Based Cyclic Oligopeptides Selectively Target G-Quadruplex", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Also Published As

Publication number Publication date
CN104250255B (en) 2016-05-25

Similar Documents

Publication Publication Date Title
Rohini et al. Antimicrobial study of newly synthesized 6-substituted indolo [1, 2-c] quinazolines
Desai et al. SelSA, selenium analogs of SAHA as potent histone deacetylase inhibitors
Zhang et al. Tricarbonylrhenium (I) complexes of phosphine-derivatized amines, amino acids and a model peptide: structures, solution behavior and cytotoxicity
AU2014306592B2 (en) Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
Can et al. The [(Cp) M (CO) 3](M= Re, 99mTc) building block for imaging agents and bioinorganic probes: perspectives and limitations
Joksović et al. Synthesis, characterization and antitumor activity of novel N-substituted α-amino acids containing ferrocenyl pyrazole-moiety
AU2010212560B2 (en) Derivatives of azaindoles as inhibitors of protein kinases Abl and Src
ES2929759T3 (en) New letting agents
WO2017133258A1 (en) 1h-indazole derivative and use thereof as ido inhibitor
Schmidt et al. Zinc (II) cyclen–peptide conjugates interacting with the weak effector binding state of Ras
KR20210010579A (en) Synthesis and use of peptide borate ester compounds
Ferri et al. Promising antiproliferative platinum (II) complexes based on imidazole moiety: synthesis, evaluation in HCT-116 cancer cell line and interaction with Ctr-1 Met-rich domain
Zhang et al. Design, synthesis and antibacterial activity of novel actinonin derivatives containing benzimidazole heterocycles
Angélica de Fátima et al. Microwave-mediated synthesis of a cyclic heptapeptoid through consecutive Ugi reactions
Singh et al. Synthesis, spectral, and in vitro antibacterial studies of organosilicon (IV) complexes with Schiff bases derived from amino acids
DK2788354T3 (en) FUNCTIONALIZATION OF CAGE AMINIGANDS FOR METALLO-RADIOPHARMACEUTICAL AGENTS
TW200827335A (en) Efficient method for producing mugineic acids
CN104250255A (en) Flexible lactam macrocycle molecule and preparation method thereof
Niklas et al. Chiral quadridentate ligands derived from amino acids and some zinc complexes thereof
Reiner et al. Phenylalanine–a biogenic ligand with flexible η 6-and η 6: κ 1-coordination at ruthenium (ii) centres
Kong et al. Neomycin B-cyclen conjugates and their Zn (II) complexes as RNA-binding agents
WO2009157505A1 (en) Telomerase inhibitor
CA2535744A1 (en) Piperazines as oxytocin agonists
CN114685382A (en) Quinazoline-4-amine derivative with HDACs (HDACs) inhibitory activity and preparation method and application thereof
Savage et al. Synthesis and characterization of novel N-para-ferrocenyl benzoyl dipeptide esters

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160525

Termination date: 20190628